Yeats said about schizophrenic psychosis, "Things fall apart; The center cannot hold". Yet, cocaine does produce psychosis in humans and in animals and effective treatment strategies are really scarce. One way to strategize treatments for any mental disorder is to reverse certain elements of the disorder using laboratory studies in animals. Since schizophrenic and cocaine psychoses have similar neurochemical and behavioral effects, an experimental design is rather straightforward. Both types of psychoses increase dopamine (DA) and serotonin (5-HT) within DA pathways, both cause hyperactivity and both are medically treated with "typical" ant/psychotic drugs. But, medical treatment is the challenge. "Typical" ant/psychotics act primarily on DA, cause movement disorders and tend to reduce 'Joie de vivre", the joy of living, whereas "atypical" ant/psychotics produce little or no movement disorders and actually enhance mood. Studies, derived during our first SCORE Award, show that "atypical" ant/psychotic drugs act on DA and 5-HT within Nucleus Accumbens (NAcc), Alo mesolimbic neurons to reverse cocaineinduced increases in DA and 5-HT release WHILE psychomotor stimulant activity is also reversed. Thus, Specific Aims 1 and 2 for our Competing Continuation, are aimed at determining how and why "typicals" and "atypicals" influence cocaine-altered neurochemistry and behavior. We will use in vivo microvoltammetry with miniature carbon sensors implanted in NAcc to detect DA and 5-HT release, in vivo, within seconds, WHILE locomotor activity is monitored in the same animal. However, since psychosis has two amazingly opposite sides, positive and negative (hyperactivity and underactivity), we will, in addition, implant miniature carbon sensors in Prefrontal Cortex (PFC). (NAcc and PFC mediate positive and negative symptoms, respectively). Studies will focus on cocaine administration, per se, and on cocaine administration, combined with receptor-specific "typicals" and "atypicals". Finally, Specific Aims 3 and 4 are aimed at further determining how ant/psychotics affect positive and negative symptoms, particularly the negative side, by using the psychotomimetic, phencyclidine (PCP) in the same paradigm. Unique advantages provided by our technology are, excellent temporal and spatial resolution; follow-up studies are enabled as well. Our hope is to find treatments for the cocaine-addicted person.